It is well known that many biological systems involve rhythmic functions which repeat in an almost regular cyclic fashion. Examples of such rhythmic functions include, but are not limited to: the motion of one limb n a gait pattern, the contraction of the heart, the movement of the chest and diaphragm in respiration, the contractions of segments of the intestine, the rise and fall of populations of different species of animals within an ecosystem and the rhythmic twitching symptomatic of certain neurological disorders. Further, in many cases, it is also known (and, in other cases, it is believed) that the rates and strengths of these rhythmic functions are modulated by underlying control functions which may, in turn, be loosely related to other rhythmic functions. Examples of such phenomena are the relationships between two different limbs in a gait pattern, the effect of respiration on heart rate, the effect of small bowel contractions on rumen contractility in cows, and the interrelationship between the population cycles of predator and prey in closed ecosystems.
Perhaps the best known of these interrelated rhythmic functions is that relationship which exists between respiration and heart rate. It is well known that for the heart to function efficiently in perfusing lung and peripheral tissues, its rate and strength of contraction must be coordinated with several factors including respiration, vascular load and tissue demand for oxygen.
A cardiovascular system that is responsive to changing physiological states requires a cooperative interaction between the cardiac, ventilatory, and vascular systems. While ventilatory activity and the vascular bed are intrinsically coupled to the heart through mechanical interactions, the major factor controlling coherence in their function is the autonomic nervous system (ANS), which communicates with the cardiac pacemaker known as the sinoatrial (SA) node. Although it is widely accepted that an altered state of neural interaction with the heart accompanies a variety of pathological conditions such as congestive heart failure and diabetes, the details of this interaction remain poorly understood.
At present, the only means of understanding the effect of the autonomic nervous system is to study the aggregate effect of neural stimulation on average heart rate, since the origin of any single nerve impulse is uncertain. Since all physiological variables that contribute to the neural traffic cannot be accounted for further refinements are difficult to achieve.
Considered separately, the heart has its own series of pacemakers, the most prominent of which is the sinoatrial node (SA node), which produces an electrical depolarization which spreads throughout the heart in a coordinated way, producing a single contraction of the heart muscle--a heartbeat. The electrical signal produced by the spreading depolarization of the heart muscle can be measured at the skin surface of a subject and visually represented in an electrocardiogram (EKG or ECG). The electrical signal related to the entire cardiac cycle consists of two distinct periods: (1) the period of electrical activity when the depolarization occurs; and (2) a period of electrical quiet in between heartbeats (the interbeat interval). The measurement of this electrical signal is often used by scientists veterinarians and physicians as a means of monitoring certain cardiac and cardiovascular functions.
Much information has been accumulated about the patterns of electrical discharges through the us of EKG's. By analyzing the waveforms of single heartbeats, those skilled in the art can interpret such waveforms and make certain diagnoses based on these single heartbeat patterns. Abnormal electrical discharges originating in the ventricle of the heart, for example, are easily detected in the EKG and produce patterns in the EKG record characteristic of ventricular beats readily distinguishable from the normal beats originating from the SA node. One catastrophic condition, ventricular fibrillation, is also easily recognized in the EKG pattern.
This effect on the heart rate induced by ventilatory activity is known as respiratory sinus arrythmia. In the simplest terms, the heart rate increases on inspiration and decreases upon expiration. Research has shown that this modulation of the heartbeat is controlled through the interplay of two branches of the autonomic nervous system, which involuntarily transmits impulses to internal organs. See, A.D. Jose and R.R. Taylor, "Autonomic blockade by propanol and atropine to study intrinsic myocardial function in man", J.Clin.Inves. 48, 2019-31 (1969); J.A. Hirsch and B. Bishop, "Respiratory sinus arrythmia in humans: how breathing pattern modulates heart rate", Am.J.Physiol 241, H620-29 (1981), both of which are incorporated by reference as if fully reproduced herein. Of the two neural branches, the parasympathetic branch, which is the craniosacral portion of the autonomic nervous system, is of particular interest. It has been found that a decrease in parasympathetic activity during the inspiratory phase accounts for much of the observed increased heart rate. See, T.A. Bruce, et al., "The role of autonomic and myocardial factors in cardiac control", J.Clin.Inves. 42, no.5, 721-26 (1963); P.G. Katona, et al., "Cardiac vagal efferent activity and heart period in the carotid sinus reflex", Am.J.Physiol. 218, no. 4, 1030-37 (1970), both of which are incorporated by reference as if fully reproduced herein.
It has also long been known that the heart rate, as measured either by EKG or by pulse counting, is not constant and varies with a number of parameters. Prominent among the parameters that affect heart rate in resting subjects is the respiratory phase. Respiration itself is a variable rhythmic event under control of the central nervous system (CNS) in all animals that occurs with much slower frequencies than the heart rate. As explained above, it is known that during the relatively long inspiratory phase of respiration in normal individuals and animals, the heart rate increases and, conversely, during expiration, the heart rate decreases. However, it is further known that this alteration in heart rate occurs as a result of neural input to the SA node, principally from the parasympathetic portion of the autonomic nervous system coursing in the right vagus nerve. In persons with certain conditions, such as diabetes, heart transplants, and some forms of congenital anomalies, this increase and decrease in heart rate in loose synchrony with the inspiration and expiration is absent or minimal in magnitude. This absence of synchrony, and a belief that quantitating the effects of neural input to the heart would lead to a better understanding of cardiac function and dysfunction have resulted in a long-felt, yet unsolved need for a method of quantitating neural effects on cardiac rhythm. Those of ordinary skill recognize that more specific diagnostic and prognostic information about human and veterinary patients suffering from cardiac and other diseases can be obtained via such quantiative methods which, prior to the present invention, was unobtainable in reliable form.
The neural conduction system of the heart originates at the sinoatrial (sinus or SA) node which is located at the junction of the superior vena cava (SVC) and the right atrium. This node is the connection point for the right vagus nerve, which communicates parasympathetic neural information. At least two distinct neural components are expected to be related to the ventilatory phase. The first of these is initiated by signals transmitted to the brain by the lung and thoracic stretch receptors. These receptors generate afferent neural impulses in response to air intake during ventilation, which communicate with the sinus node via the brain stem. A second neural component originates at the carotid and atrial baroreceptors, the sensory receptors located in the arteries and within the heart which respond to pressure variations and relay signals representative of this information to the brain. The brain then transmits this information to the sinus node via the parasympathetic nervous system. This neural control of the natural pacemaker activity of a healthy heart adds great complexity to any detailed understanding of the coupling between the cardiovascular and ventilatory systems.
A crude method of determining the effects of parasympathetic nerve stimulation on heart rate, known to those skilled in the art, is to measure heart rate by counting beats under normal, at rest conditions and then comparing this rate with the observed heart rate while applying pressure to one eyeball, which is believed to induce a parasympathetic neural decrease in heart rate. It is also known, for example, that direct stimulation of the right vagus nerve will dramatically slow the heart rate in individuals with functional neural input to the SA node.
Another method, more quantitative than either of the above and applicable to human medicine, has been used by certain cardiologists and physiologists, but has met with minimal success. This method relies on frequent analysis of the electrocardiogram and of the respiratory cycle. Utilizing the principle of Fourier Analysis, the EKG is broken down into various imaginary constant components of differing frequencies and amplitudes. On of ordinary skill will readily appreciate that since the actual depolarization of the cardiac mass occurs in a regular pattern of much shorter duration than the overall cardiac cycle, the frequency components of the electrically active period in the EKG are of higher frequency than the overall cardiac cycle. Thus, changes in the heart rate are most easily observed as changes in the heartbeat interval (hbi). Consequently, in a power spectrum analysis of many sequential heartbeats, the power in the higher frequencies will be due principally to the electrical signal produced during depolarization, while the power in the lower frequencies will be more related to the interbeat interval. If the heart rate is varying considerably, the power in the lower frequencies will be spread out, while if there is no variation in heart rate (and, consequently, no variation in interbeat interval) the power in the lower frequencies will be more concentrated.
There are, however, severe deficiencies in the results obtained from this method. First, the heartbeat is not exactly periodic; since the calculations that must be performed to estimate frequency information can only be done practically through digital Fourier Transforms--which assume perfectly periodic signals--several approximations must be made in data interpretation. These approximations, however, may mask the underlying behavior of the system. Second, by using power spectral information, all phase information is lost. Since phase may be an important consideration in obtaining meaningful results, any result obtained which is unrelated to this parameter is at best incomplete. Third, because the power spectrum is dependent upon the amplitude of the electrical signal, this method is extremely sensitive to such factors as electrode placement, patient position, and disease conditions such as fluid in the chest or pericardium. Finally, these difficulties are exacerbated exponentially when similar approximations to the power spectrum are used to correlate the frequencies of the respiratory cycle with those of the cardiac cycle through ratio calculations. Thus, this method is also inadequate to fully study the effects of parasympathetic nerve stimulation on the heart.
Studies of cardioventilatory interaction typically utilize data taken on mechanically ventilated subjects. In order to provide reliable results, the extent to which the neural activity associated with free breathing has been reproduced must be determined. During both free breathing and inspiration imposed by a mechanical positive pressure ventilator, pulmonary and thoracic stretch receptors which initiate the transmission of afferent impulses to the respiratory center in the brain stem via the right and left vagus nerves are activated. From the brain stem, efferent nerve discharges are delivered through the phrenic nerve to the diaphragm and through the right vagus nerve to the SA node. This feedback mechanism results in synchronization between ventilation and the neural control of the heartbeat, whether the ventilation is naturally o externally controlled. In an artificially ventilated subject, neural activity which is normally associated with "free" breathing is essentially reproduced when the respiration is externally and consistently imposed, but this neural activity is now synchronized with the externally imposed rhythm.
The neural discharges which govern cardioventilatory interaction ar mediated through the parasympathetic branch of the autonomic nervous system. These neural discharges result in the deposition of acetylcholine at the SA node, which induces perturbations in the ion flows across the cell membranes, thus altering the excitation interval of the cardiac pacemaker. In general, the effect of the neural impulse is dependent upon the phase within the heartbeat interval at which the acetylcholine is delivered, as well as upon the heart rate and the sympathetic tone, but the result is a discrete change in the heartbeat interval which spans the neural discharge.
Therefore, although comparing neural data from mechanically respirated and naturally respirated subjects is conceptually valid, there is still a long felt but unsolved need for methods which allow neural data to be analyzed and processed, and to identify discrete neural impulses associated with specific pathologies.
Thus, it is known that the normal functioning of the cardiovascular system requires a cooperative interaction between the heart and the respiratory system. It is further known that the respiratory activity may couple directly to the heart through mechanical interactions, a condition known as phase locking. For example, there can be effects due to the local physical environment of the heart changing as the chest cavity expands during breathing. As explained at the outset, phase locking is a very general phenomenon in any dynamical system, whether physical or biological in origin. See Levy, et al., "Paradoxical effects of vagus nerve simulation of heart rate in dogs," Circ. Res., vol. 25, pp. 303-14 (1969); Jalife et al., "Dynamic vagal control of pacemaker activity in the mammalian sinoatrial node," Circ. Res., vol. 52, pp. 642-56 (1983); and Glass et al., "Global bifurcations of a periodically forced biological oscillator," Phys. RevA, vol. 29, p. 1348 (1984), all of which are incorporated by reference as if fully reproduced herein. In addition to these direct mechanical couplings, the natural pacemaker of the heart is also affected via the nervous system. The basic physiological pathways involved in this feedback loop are known; in a healthy heart there are direct repetitive neural impulses emanating from the brain stem which are synchronous with ventilation, these neural couplings are mediated through the carotid and atrial barroreceptors which have direct feedback to the SA node. The simultaneous interaction of all these influences results in a highly complex dynamical system.